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Substrate Selectivity of Coumarin Derivatives by Human CYP1 Enzymes: In Vitro Enzyme Kinetics and In Silico Modeling.

ABSTRACT: Of the three enzymes in the human cytochrome P450 family 1, CYP1A2 is an important enzyme mediating metabolism of xenobiotics including drugs in the liver, while CYP1A1 and CYP1B1 are expressed in extrahepatic tissues. Currently used CYP substrates, such as 7-ethoxycoumarin and 7-ethoxyresorufin, are oxidized by all individual CYP1 forms. The main aim of this study was to find profluorescent coumarin substrates that are more selective for the individual CYP1 forms. Eleven 3-phenylcoumarin derivatives were synthetized, their enzyme kinetic parameters were determined, and their interactions in the active sites of CYP1 enzymes were analyzed by docking and molecular dynamic simulations. All coumarin derivatives and 7-ethoxyresorufin and 7-pentoxyresorufin were oxidized by at least one CYP1 enzyme. 3-(3-Methoxyphenyl)-6-methoxycoumarin (19) was 7-O-demethylated by similar high efficiency [21-30 ML/(min·mol CYP)] by all CYP1 forms and displayed similar binding in the enzyme active sites. 3-(3-Fluoro-4-acetoxyphenyl)coumarin (14) was selectively 7-O-demethylated by CYP1A1, but with low efficiency [0.16 ML/(min mol)]. This was explained by better orientation and stronger H-bond interactions in the active site of CYP1A1 than that of CYP1A2 and CYP1B1. 3-(4-Acetoxyphenyl)-6-chlorocoumarin (20) was 7-O-demethylated most efficiently by CYP1B1 [53 ML/(min·mol CYP)], followed by CYP1A1 [16 ML/(min·mol CYP)] and CYP1A2 [0.6 ML/(min·mol CYP)]. Variations in stabilities of complexes between 20 and the individual CYP enzymes explained these differences. Compounds 14, 19, and 20 are candidates to replace traditional substrates in measuring activity of human CYP1 enzymes.

SUBMITTER: Juvonen RO

PROVIDER: S-EPMC8153946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background The unique anthropological coronavirus which has been titled as SARS-CoV-2 was originally arisen in late 2019 in Wuhan, China affecting respiratory infection named as COVID-19. Coronavirus is disturbing human life in an exceptional method and has converted a public health global crisis. Natural products are ahead consideration due to the huge beneficial window and effective anti-inflammatory, immunomodulatory, antioxidant and antiviral possessions. Consequently, the present study was intended to display inhibition ability of natural products coumarins and their analogues against SARS coronavirus. Methods The present study, aims to forecast theoretical assembly for the protease of COVID-19 and to discover advance whether this protein may assist as a target for protease inhibitors such as psoralen, bergapten, imperatorin, heraclenin, heraclenol, saxalin, oxepeucedanin, angelicin, toddacoumaquinone, and aesculetin. The docking score of these natural coumarin analogues compared with standard Hydroxychloroquine. Whereas the 3D assembly of main protease of SARS coronavirus was forecast with SWISS MODEL web server, and molecular interaction studies amongst target protein and ligands were done with AutoDock Vina software. Results The study more exposed that all the inhibitors acquired with negative dock energy against the target protein. Molecular docking investigation displayed that natural coumarin analogue toddacoumaquinone displayed a remarkable inhibition ability with the binding energy of ?7.8 kcal/mol than other compounds against main protease of SARS coronavirus in intricate with ?-ketoamide (PDB ID: 5N5O). The synthetic coumarin analogue (1 m) also displayed the comparable inhibition ability with a binding energy of ?7.1 kcal/mol against main protease of SARS coronavirus in intricate with ?-ketoamide. Keeping the overhead results of ADME and toxicity, all tested compounds were recognized as drug-like nature, passing Lipinski’s “Rule of 5” with 0 violation except ?-ketoamide passes Lipinski’s “Rule of 5” with 1 violation MW > 500. The projected constraints are within the assortment of recognized values. Conclusions Based upon the results of the manifold sequence alliance, natural and synthetic coumarin binding sites were preserved. The present in silico examination thus, delivers structural awareness about the protease of COVID-19 and molecular relations with some of the recognised protease inhibitors.

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Substrate Selectivity of Coumarin Derivatives by Human CYP1 Enzymes: In Vitro Enzyme Kinetics and In Silico Modeling.

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